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(11) | EP 1 531 151 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | A process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl] methyl piperidine hydrochloride (donepezil hcl) |
| (57) This invention describes a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl
piperidine hydrochloride (Donepezil HCI) of the formula I
comprising hydrogenerating 5,6-dimethoxy-2-(pyridin-4-yl)methylene indan-1-one with a noble metal catalyst in a solvent at 20-100°C and 0.7-6.2 bar pressure to form 4-((5,6-dimethoxy-1-indanon)-2-yl)methyl piperidine which is alkylated with an alkylating agent in an organic solvent at 20-80°C. |
Field of Invention
[0001] This invention relates to a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride (Donepezil HCl) of the formula
[0002] A compound of the formula I commonly known as Donepezil HCl is used for treatment of Central Nerve System (CNS) disorders.
Descripition of the Related Art
[0003] U.S. Pat. No. 4,895,841 describes preparation of Donepezil HCl by reacting 5,6-dimethoxy-1-indanone with 1-benzyl-4-formylpiperidine in the presence of a strong base such as lithium diisopropyl amide followed by reduction with palladium carbon catalyst (Examples 3 and 4). Overall yield of Donepezil HCl is reported to be 50.8%. (62% x 82%).
[0004] U.S. Pat. No. 5,606,064 teaches the preparation of Donepezil HCl by the reaction of 5,6-dimethoxy-1-indanone with pyridin-4-aldehyde. The resulting 5,6-dimethoxy-2-(pyridin-4-yl)methyleneindan-1-one is reacted with benzyl bromide to afford 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-ylidine]methyl pyridinium bromide which on reduction with platinum oxide catalyst afforded Donepezil HCl. (Examples 2, 4 and 6). Overall yield of Donepezil HCl 58.5% (87% x 83% x81%).
[0005] PCT Publication No WO 97/22584 reports preparation of Donepezil HCl by reacting pyridine-4-aldehyde with malonic acid. The resulting 3-(pyridin-4-yl)-2-propionic acid was reduced with rodium on carbon under hydrogen atmosphere to give 3-(piperidin-4-yl)-2-propionic acid which on reaction with methyl chlorocarbonate gave 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid. On reacting 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid with oxalyl chloride, methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate is obtained which on reaction with 1,2-dimethoxy benzene in the presence of aluminium chloride afforded 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate. On reacting 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate with tetramethyl diamino methane, 4-[2-(3,4-dimethoxy benzoyl)allyl]piperidin-1-carboxylate is obtained which on treatment with sulphuric acid gave methyl 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate. On decarboxylating 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate, 5,6-dimethoxy-2-(piperidin-4-yl methyl)-1-indanone is obtained which on treatment with benzyl bromide afforded Donepezil HCl (Example 1 to 6). Overall yield of Donepezil HCl 19.3% (70% x 84% x 100% x 68% x 79% x 61 %).
[0006] U.S. Pat. No. 6,252,081 teaches the preparation of Donepezil HCl by the reaction of 1-indanone derivative with carbonate ester. The resulting 2-alkoxycarbonyl-1-indanone derivative is halogenated with (4-pyridyl)methyl or a salt thereof and decarboxylated successively to give 2-(4-pyridyl)methyl-1-indanone derivative. On reacting the 2-(4-pyridyl)methyl-1-indanone derivative with benzyl bromide, their quaternary ammonium salts are formed, which on reduction with platinum oxide catalyst gives Donepezil HCl (Examples 1 to 3). Overall yield of Donepezil HCl 82% (98% x 85% x 100% x 99%).
[0007] The prior art processes employs 1-benzyl-4-formyl piperidine as starting material whose synthesis is low yielding and involves use of lithium diisopropyl amide. The reaction of 1-benzyl-4-formyl piperidine with 5,6-dimethoxy-1-indanone also involves use of lithium diisopropyl amide and cryogenic temperatures, which are expensive and are not economically viable. Lithium diisopropyl amide is toxic and needs to be carefully handled. Many a time selective reduction of double bond to yield 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride is difficult to achieve. Besides, the selective reduction of double bond to give 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride is many a time coupled with formation of side products which are difficult to separate. Yield of the product is also affected due to the formation of the side products. Use of oxalyl chloride chemistry is difficult for scale up. Besides the oxalyl reaction also involves many protection deprotection chemistry and the over all yield is very low. Raw materials like methyl chlorocarbonate or tetramethyl diaminomethyl are expensive and difficult to source commercially. The prior art processes are also time consuming and difficult to carry out as they involve many steps.
Objects of the Invention
[0008] An object of the invention is to provide a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride which eliminates formation of byproducts and gives high yield of the product and is efficient and economical.
[0009] Another object of the invention is to provide a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride which employs less number of reaction steps and is less time consuming, easy and convenient to carry out.
[0010] Another object of the invention is to provide a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride which eliminates use of hazardous reagents and is safe to carryout.
[0011] Another object of the invention is to provide a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-y)]methyl piperidine hydrochloride which employs cheaper and easily available raw materials.
[0012] Another object of the invention is to provide a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride which is suitable for industrial scale up.
Detailed Description of the Invention
[0013] According to the present invention, there is provided a process for the preparation of 1-benzyl-4-[5,6-dimethoxy-1-indanon)-2-yl] methylpiperidine hydrochloride (Donepezil HCl of the formula I)
comprising hydrogenating 5,6-dimethoxy-2-(pyridin-4-yl)methylene indan-1-one with a noble metal catalyst or a non-oxide derivative of a noble metal catalyst in a solvent at 20-100°C and 10-90 psi guage pressure to form 4-[(5,6-dimethoxy-1-indanon)-2-yl] methyl piperidine of the Formula II
which is alkylated with an alkylating agent in an organic solvent at 20-80°C.
[0014] Suitable solvents used in the hydrogenation of compound of the formula II with a noble metal catalyst or a non-oxide derivative of a noble metal catalyst may be C1-C4 aliphatic alcohol such as tetrahydrofuran or methanol, organic acid such as acetic acid, dilute HCl, ethyl acetate, aliphatic ketone, or mixtures thereof. Preferably, the suitable solvent used with a noble metal catalyst or a non-oxide derivative of a noble metal catalyst is acetic acid.
[0015] A noble metal catalyst used in hydrogenation may be palladium, rhodium or ruthenium metal. A non-oxide derivative of a noble metal catalyst may also be used, such as a chloride or a sulphate of a noble metal selected from the group consisting of palladium, rhodium and ruthenium.
[0016] The noble metal catalyst or non-oxide derivative of a noble metal catalyst can be supported on a carrier, such as carbon, calcium carbonate, barium sulphate or alumina. A preferred carrier is carbon.
[0017] A preferred noble metal catalyst is palladium. A preferable condition for hydrogenation with a noble metal catalyst is a 10% concentration of palladium on carbon.
[0018] Usually hydrogenation using a noble metal catalyst or a non-oxide derivative of a noble metal catalyst is carried out at 20-100° C and 10-90 psi gauge pressure. Preferably hydrogenation using a noble metal catalyst or a non-oxide derivative of a noble metal catalyst is carried out at 70-80° C and 45-55 psi guage. More preferably hydrogenation using a noble metal catalyst or a non-oxide derivative of a noble metal catalyst is carried out at 75° C and 50 psi guage.
[0020] The organic solvent used in the alkylation reaction may be dichloromethane, triethyl amine or mixtures thereof preferably dichloromethane and triethyl amine mixture.
[0022] The process of the preferred embodiments eliminates formation of byproducts and gives high yield of the product (about 92%). It employs cheaper and easily available raw materials and eliminates use of hazardous reagents. It is, therefore, efficient and economical and safe to.carryout. It comprises only two steps and is, therefore, less time consuming and is easy and convenient to carryout. For the above reasons, it is also suitable for industrial scale up.
[0023] The following examples are illustrative of the invention but not limitative of the scope thereof.
EXAMPLE 1
4-[(5,6-Dimethoxy-1-indanon)-2-yl] methyl piperidine (II)
[0024] 10 g (0.035 mole) of 5,6-dimethoxy-2-(pyridin-4-yl) methylene indan-1-one and 1 g Palladium on Carbon (10%) were suspended in acetic acid (300 ml.) at 50 psi and at 75° C. for 4 hrs. Palladium was filtered off and the filtrate was concentrated. The residue was treated with 10 % aqueous sodium hydrogen carbonate solution and the solution was extracted 3 times with dichloromethane (3x100ml), dried over sodium sulphate and concentrated to dryness.
Yield of 4-[(5,6-Dimethoxy-1-indanon)-2-yl] methyl piperidine was 10.1 g (99 %). Corresponding HCl of I has, mp 248-250° C, lit. mp. 249-50° C, (synthesis adopting different synthetic route, USP-4,895,841).
1H NMR (base, 200 MHz CDCl3) δ (ppm) 7.1(s,1H), 6.9 (s, 1H), 3.9 (s,3H), 3.8 (s,3H), 3.0-3.2 (m,3H), 2.6-2.7 (m,4H), 2.2 (bs;1 H, exchanges with D2O), 1.6-1.7 (m,4H), 1.2-1.3 (m,3H).
EXAMPLE 2
1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl)methyl piperidine hydrochloride
[0025] 10 g (0.0346 mol) of 4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine was dissolved in 100 ml dichloromethane followed by 6.5 g benzyl bromide and 13 g triethyl amine. The reaction mixture was refluxed for 4 hrs. The reaction mixture was filtered off and the filtrate was concentrated to yield 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine free base which was redissolved in 100 ml methanol followed by addition of 10 ml methanolic--HCl (10%). The reaction mixture was cooled at 10.degree. and the resulting solid was filtered and washed with cooled methanol.
1. A process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl] methylpiperidine
hydrochloride (Donepezil HCl) of the formula I
comprising hydrogenating 5,6-Dimethoxy-2-(pyridin-4-yl)methylene indan-1-one with a noble metal catalyst or a non-oxide derivative of a noble metal catalyst in a solvent at 20-100° C and 10-90 psi gauge pressure to form 4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine of the formula II
which is alkylated with an alkylating agent in an organic solvent at 20-80° C.
comprising hydrogenating 5,6-Dimethoxy-2-(pyridin-4-yl)methylene indan-1-one with a noble metal catalyst or a non-oxide derivative of a noble metal catalyst in a solvent at 20-100° C and 10-90 psi gauge pressure to form 4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine of the formula II
which is alkylated with an alkylating agent in an organic solvent at 20-80° C.
2. The process according to Claim 1, wherein the solvent used in the hydrogenation step
is selected from the group consisting of C1- C4 aliphatic alcohols, organic acid, dilute HCl, ethyl acetate, aliphatic ketone and
mixtures thereof.
3. The process according to Claim 2, wherein the solvent used in the hydrogenation step
is acetic acid.
4. The process according to any one of claims 1 to 3, wherein the noble metal is selected
from the group consisting of palladium, rhodium, and ruthenium metal.
5. The process according to Claim 4, wherein the noble metal catalyst is palladium metal.
6. The process according to Claim 5, wherein the palladium metal is at 10% concentration.
7. The process according to any one of claims 1 to 3, wherein the non-oxide derivative
of a noble metal catalyst is a chloride or a sulphate of a noble metal selected from
the group consisting of palladium, rhodium and ruthenium.
8. The process according to any one of claims 1 to 7, wherein the noble metal catalyst
or the non-oxide derivative of a noble metal catalyst is supported on a carrier selected
from the group consisting of carbon, calcium carbonate, barium sulphate and alumina.
9. The process according to Claim 8, wherein the carrier is carbon.
10. The process according to any one of claims 1 to 9, wherein the hydrogenation is carried
out at 70-80°C.
11. The process according to Claim 10, wherein the hydrogenation is carried out at 75°C.
12. The process according to any one of claims 1 to 11, wherein the hydrogenation is carried
out at 45-55 psi gauge.
13. The process according to Claim 12, wherein the hydrogenation is carried out at about
50 psi gauge.
14. The process according to any one of claims 1 to 13, wherein the alkylation is carried
out with benzyl bromide as alkylating agent.
15. The process according to any one of claims 1 to 14, wherein the alkylation is carried
out in a dichloromethane/triethyl amine mixture.